1. Field of the Invention
This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by α4β7. Accordingly, compounds of this invention are useful in the treatment and prevention of diseases mediated by α4β7 binding and cell adhesion and activation such as multiple sclerosis, asthma, allergic rhinitis, rheumatoid arthritis, septic arthritis, restenosis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, dermatitis, psoriasis, and the like.
2. State of the Art
The following publications, patents and patent applications are cited in this application as superscript numbers:    1 Tidswell, et al., J. of Immunology, 1497-1505 (1997)    2 Springer, Nature, 346:425-434 (1990)    3 Osborn, Cell, 62:3-6 (1990)    4 Vedder, et al., Surgery, 106:509 (1989)    5 Pretolani, et al., J. Exp. Med., 0.180:795 (1994)    6 Abraham. et al., J. Clin. Invest., 93:776 (1994)    7 Mulligan, et al., J. Immunology, 150:2407 (1993)    8 Cybulsky, et al., Science, 251:788 (1991)    9 Li, et al., Arterioscler. Thromb., 13:197 (1993)    10 Sasseville, et al., Am. J. Path., 144:27 (1994)    11 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)    12 Burkly, et al., Diabetes, 43:529 (1994)    13 Baron, et al., J. Clin. Invest., 93:1700 (1994)    14 Hamann, et al., J. Immunology, 152:3238 (1994)    15 Yednock, et al., Nature, 356:63 (1992)    16 Baron, et al., J. Exp. Med., 177:57 (1993)    17 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)    18 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993)    19 Elices, et al, J. Clin. Invest., 93:405 (1994)    20 Postigo, et al., J. Clin. Invest., 89:1445 (1991)    21 Paul, et al., Transpl. Proceed, 25:813 (1993)    22 Okarhara, et al., Can. Res., 54:3233 (1994)    23 Paavonen, et al., Int. J. Can., 58:298 (1994)    24 Schadendorf et al., J. Path., 170:429 (1993)    25 Bao, et al., Diff, 52:239 (1993)    26 Lauri, et al., British J. Cancer, 68:862 (1993)    27 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)    28 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996    29 International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
Integrins are heterodimeric adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. The β7 integrin subfamily has two known members: α4β7 and αEβ7. These β7 integrins are expressed primarily by leukocytes. β7 integrins are unique among known integrins in their ability to recognize certain ligands expressed on the surface of endothelial and epithelial cells in mucosal organs.1 
α4β7 is a lymphocyte homing receptor and plays a crucial role in the migration of these cells to the intestine and associated lymphoid tissue, such as Peyer's patches in the intestine. α4β7 mediates adhesion to a ligand on Peyer's patch high endothelial venules (“HEV4”). The ligand on Peyer's patch HEV is MAdCAM-1, a glycoprotein in the Ig superfamily. MAdCAM-1 is expressed on Peyer's patch HEV, mesenteric lymph node HEV, and lamina propria venules within the gut. Antibodies against α4 or β7 subunits inhibit attachment of circulating lymphocytes to Peyer's patch HEV in vivo.1 
Memory T cells that circulate preferentially to intestinal tissues express high levels of α4β7, whereas those that circulate to other organs are mostly α4β1. These α4β7 memory T cells express a related integrin, α4β1, which is not able to mediate cell adhesion to MAdCAM-1. However, both α4β7 and α4β1, can mediate adhesion to VCAM-1 and to fibronectin.1 
Intercellular adhesion mediated by α4β7 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer2 and Osborn.3 
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult.4 Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma,5-7 Alzheimer's disease, atherosclerosis,8-9 AIDS dementia,10 diabetes (including acute juvenile onset diabetes),11-13 inflammatory bowel disease (including ulcerative colitis and Crohn's disease),4 multiple sclerosis,15-16 rheumatoid arthritis,17-20 tissue transplantation,21 tumor metastasis,22-27 meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Despite advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory conditions.28,29 Novel alpha4 antagonists are needed for the development of additional treatment options for inflammatory diseases, such as MS, asthma, Crohn's disease and rheumatoid arthritis. Furthermore, assays useful for the diagnosis of α4β7 mediated conditions are needed. The current invention addresses these and other needs.